The sequencing of the human genome provides a 'post-genomic' framework to identify genetic and epigenetic variations and discover the role they play in human diseases, in particular complex diseases. We will investigate epigenetic phenomena using an integrated approach by combining knowledge from genomic sequences and population genetic variations. Studying the epigenetic patterns within the genome will provide valuable insight into our understanding of genome organization and function. Focused investigation of known imprinted regions may also reveal novel sequence signatures that may be involved in epigenetic modifications. The information gleaned from these investigations may lead to biologically grounded hypotheses of complex human diseases that are due to aberrant epigenetic changes. The majority of common human diseases affecting a large segment of our population, including cardiovascular, metabolic, and neurological disorders, as well as cancer among others, are complex in etiology and involve interaction of multiple genetic, cultural, and/or environmental factors, as well as epigenetic effects. The goal of the proposed research plan is to develop statistical and computational tools that integrate related knowledge from the quantitative and biological sciences to aid in the study of the genetic basis of common complex diseases. An integrated research paradigm that synthesizes analytical approaches from bioinformatics and genetic epidemiology as well as epigenetic models is likely to be a more powerful approach for understanding the etiological basis of complex diseases.